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Cabergoline

Cabergoline is a long-acting dopamine agonist.

Arana-Valencia Nicole
Evaluation of Dopaminergic and Antidopaminergic Agents for Use in Equine Metabolic Physiology
PhD dissertation 4658 Louisiana State University 29 June 2018

Arana-Valencia N, Thompson Jr DL, Oberhaus EL
Long-term and Short-term Dopaminergic (Cabergoline) and Antidopaminergic (Sulpiride) Effects on Insulin Response to Glucose, Glucose Response to Insulin, or Both in Horses
Journal of Equine Veterinary Science Volume 59, December 2017, Pages 95-103
Neither long-term nor short-term treatment with cabergoline affected insulin sensitivity in either insulin-sensitive or insulin-insensitive horses.

Arana-Valencia N, Thompson DL, Oberhaus EL, Gilley RM
Long-term Treatment of Insulin-insensitive Mares with Cabergoline: Effects on Prolactin and Melanocyte Stimulating Hormone Responses to Sulpiride and on Indices of Insulin Sensitivity
Journal of Equine Veterinary Science May 2014 Vol 34, 5, 680-686. https://doi.org/10.1016/j.jevs.2013.12.015

Repeatability of Prolactin Responses to Sulpiride in Mares and Geldings and the Effect of Pergolide and Cabergoline
Rebekah Hebert MSc Thesis May 2012

Carbohydrates

Carbohydrates are the principle source of energy for horses and comprise broadly of nonstructural carbohydrates - sugars, starch, fructans - and fermentable carbohydrates - cellulose, hemicellulose, pectins and lignin.

(Simple) sugars are hydrolyzable as well as fermentable, are water soluble (so can be removed/reduced by soaking in water) and are either:
monosaccharides - glucose and fructose (and galactose, mannose, arabinose and xylose) - can be absorbed from the intestine without digestive enzyme activity; or
disaccharides - sucrose (digested to fructose & glucose), maltose (digested to glucose & glucose) and lactose (digested to galactose & glucose).
Plants contain glucose, fructose and sucrose.
In a feed analysis, sugars make up the ESC (ethanol soluble carbohydrates), which form part of the WSC (water soluble carbohydrates), along with fructans.

Fructans are water soluble oligo- or poly-saccharide carbohydrates that contain multiple fructose units. Fructans are the primary storage carbohydrate of cool season grasses, particularly during periods of stress (drought, freezing). The structure of fructans varies among plant species - in grasses fructans are levans or phleins, whereas in broad-leaved plants fructans are inulin.

Starch is a polysaccharide carbohydrate, is hydrolyzable by digestive enzymes but is not water soluble. Starches are the primary storage carbohydrate of warm season grasses and legumes (e.g. alfalfa, clover).

NSC (nonstructural carbohydrates) = WSC (water soluble carbohydrates) + starch
WSC = (broadly) ESC (ethanol soluble carbohydrates) + fructans
ESC is a subset of WSC

Hoffman Rhonda M (2009)
Carbohydrate metabolism and metabolic disorders in horses
Revista Brasileira de Zootecnia, 38(spe), 270-276.

McIntosh Bridgett PhD dissertation December 2006
Circadian and Seasonal Variation in Pasture Nonstructural Carbohydrates and the Physiological Response of Grazing Horses

Carbohydrate overload

Vet Clin North Am Equine Pract. 2010 Apr;26(1):65-78
Carbohydrate alimentary overload laminitis
Pollitt CC, Visser MB

J Anim Sci. 2002 Oct;80(10):2656-62 (PubMed) Full paper
Production of amines in equine cecal contents in an in vitro model of carbohydrate overload
Bailey SR, Rycroft A, Elliott J.

CGIT - Combined glucose-insulin (tolerance) test

The combined glucose-insulin (tolerance) test (CGIT) is a dynamic test of insulin dysregulation developed by Eiler et al. as a simplified combination of the insulin sensitivity test (IST) and the frequently sampled intravenous glucose tolerance test (FSIGTT). The CGIT measures insulin sensitivity by recording the time that blood glucose concentrations return to baseline after giving a specified dose of glucose and insulin, and measuring the insulin concentration after 45 minutes (and 75 minutes). It primarily provides an indirect measure of tissue insulin resistance (Bertin and de Laat 2017).

The CGIT is usually carried out under fasting conditions - the horse should be stabled and given one flake of hay around 10 pm, then the test carried out the following morning before the horse is fed. A blood sample is collected to measure baseline glucose (and insulin). 150 mg/kg bodyweight glucose (50% dextrose solution) (150 ml 50% per 500 kg horse) is injected IV immediately followed by 0.1 IU/kg bodyweight insulin (0.5 ml 100 IU/ml per 500 kg horse). Blood is collected at frequent intervals - usually 1, 5, (10), 15, 25, 35, 45, 60, 75, 90, 105, 120, (135 and 150) minutes after the infusion of glucose and insulin and the glucose concentration tested to determine the time at which the glucose concentration returns to baseline, and the insulin concentration is measured from the 45 minute (and 75 minute) collection.

Tissue insulin resistance is diagnosed if the blood glucose concentration is still above baseline after 45 minutes, and/or if the insulin concentration at 45 minutes is > 100 µIU/ml. However, according to Bertin and de Laat 2017, these cut-off values have not been fully validated in horses.

Using the duration of the positive phase (relative hyperglycaemia), the CGIT shows sensitivity of 85.7% and specificity of 40%, compared to the FSIGTT. Using the insulin value at 45 minutes, the CGIT shows sensitivity of 28.5% and specificity of 100%, compared to the FSIGTT.
(Sensitivity or the true positive rate measures the proportion of actual positives that are correctly identified as being positive - here, horses with tissue insulin resistance correctly identified as being positive for tissue insulin resistance; specificity or the true negative rate measures the proportion of actual negatives that are correctly identified as being negative - here, healthy horses without tissue insulin resistance correctly identified as being negative for tissue insulin resistance).

Serum glucose peaks 1 - 5 minutes after glucose/insulin administration and reaches 2 - 2.5 x the baseline value, remains above baseline for around 30 - 45 minutes and then falls below baseline for a further 1 - 2 hours in a normal horse. An insulin resistant horse is likely to have a higher serum glucose peak, serum glucose is likely to remain above baseline for more than 45 minutes, and fall below baseline for less than 1 - 2 hours, if at all.
The glucose concentrations can be measured by laboratory analysis, hand-held glucometer or possibly CGMS (Johnson et al. 2011).

CGIT in research:

Olley RB, Carslake HB, Ireland JL, McGowan CM
Comparison of fasted basal insulin with the combined glucose-insulin test in horses and ponies with suspected insulin dysregulation
The Veterinary Journal Volume 252, October 2019 (online 05 August 2019). https://doi.org/10.1016/j.tvjl.2019.105351

Bertin FR, de Laat MA
The diagnosis of equine insulin dysregulation
Equine Veterinary Journal Volume 49, Issue 5 September 2017 Pages 570–576

Dunbar LK, Mielnicki KA, Dembek KA, Toribio RE, Burns TA
Evaluation of Four Diagnostic Tests for Insulin Dysregulation in Adult Light‐Breed Horses
Journal of Veterinary Internal Medicine. 2016;30(3):885-891. doi:10.1111/jvim.13934

Bröjer J, Lindåse S, Hedenskog J, Alvarsson K, Nostell K
Repeatability of the combined glucose-insulin tolerance test and the effect of a stressor before testing in horses of 2 breeds
J Vet Intern Med. 2013 Nov-Dec;27(6):1543-50. doi: 10.1111/jvim.12172

Funk RA, Wooldridge AA, Stewart AJ, Behrend EN, Kemppainen RJ, Zhong Q, Johnson AK.
Seasonal changes in the combined glucose-insulin tolerance test in normal aged horses.
J Vet Intern Med. 2012 Jul-Aug;26(4):1035-41. doi: 10.1111/j.1939-1676.2012.00939.x. Epub 2012 May 18. PMID: 22594619.

Johnson et al. 2011 - mean blood glucose concentration from 7 obese female ponies, aged 13 - 20, 5 of which had chronic laminitis and 5 of which had PPID, fed grass hay throughout the test, was approx. 100 mg/dl baseline and approx. 150 mg/dl 45 minutes after glucose/insulin administration, with a return to baseline at approx. 120 minutes.

Equine Veterinary Journal Volume 44, Issue Supplement s42, Article first published online: 13 SEP 2012 (Abstract #32 from BEVA 2012)IS THE COMBINED GLUCOSE AND INSULIN TEST (CGIT) USEFUL FOR EVALUATION OF ENDOCRINOPATHIC LAMINITIS AND MONITORING THE RESPONSE TO TREATMENT?
Keen, J., Stratford, C. and Lyle, C.
EMS horses had higher glucose at 45 minutes compared to PPID horses. Resting glucose and insulin results were not significantly affected by treatment, but CGIT results improved in all cases following treatment. It was concluded that the CGIT may offer more information than resting glucose and insulin alone when monitoring treatment response for EMS and PPID cases.

Funk RA, Wooldridge AA, Stewart AJ, Behrend EN, Kemppainen RJ, Zhong Q, Johnson AK
Seasonal Changes in the Combined Glucose-Insulin Tolerance Test in Normal Aged Horses
Journal of Veterinary Internal Medicine, 26: 1035–1041 (2012) (PubMed)
"No clinically relevant differences were seen in the results of the CGIT, suggesting that season minimally affects results of this test in normal aged horses in the southeastern United States."

J Vet Intern Med 2011;25:162–165
Clinical Assessment of Blood Glucose Homeostasis in Horses: Comparison of a Continuous Glucose Monitoring System with a Combined Intravenous Glucose and Insulin Test Protocol
P.J. Johnson, C.E. Wiedmeyer, A. LaCarrubba, N.T. Messer, H.A. Dingfelder, A.M. Cogswell,J.R.R. Amorim, and V.K. Ganjam

(PubMed) J Am Vet Med Assoc. 2006 May 1;228(9):1383-90.
Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance.
Frank N, Elliott SB, Brandt LE, Keisler DH.

(PubMed) Am J Vet Res. 2005 Sep;66(9):1598-604.
Physiologic assessment of blood glucose homeostasis via combined intravenous glucose and insulin testing in horses.
Eiler H, Frank N, Andrews FM, Oliver JW, Fecteau KA.

Charcoal - Activated

In Equine Laminitis Current Concepts (2008) Chris Pollitt suggests that "the administration of mineral oil or activated charcoal may be beneficial in cases of laminitis developing after ingestion of excess grain" (i.e. SIRS laminitis).
Section 10.4.2 - Six horses with acute colitis (fever, profuse diarrhoea, signs of endotoxaemia and circulatory shock) and no signs of laminitis were treated with cryotherapy for at least 72 hours and given IV fluids, antibiotics, NSAIDs, paraffin oil and activated charcoal. Laminitis did not develop in any of the 6 horses. Incidence of laminitis following acute colitis without similar treatment was estimated at 40-50%.

Section 10.11 - "activated charcoal is an effective adsorbent of a range of toxins and may be useful in cases of grain overload if administered promptly. In Australia, doses of 1- 5 g/kg/day have been used to treat plant toxicoses in large animals. The higher dose is indicated if a large quantity of grain has been consumed. However activated charcoal has not been tested against alimentary laminitis, so its true effectiveness is unknown."

TLS is not aware of any suggestion that activated charcoal is effective in treating endocrine laminitis - most if not all cases of pasture associated laminitis are endocrine.

Is Activated Charcoal Safe for Colicky, Toxic Horses? Kentucky Equine Research July 2016

Edmunds JL, Worgan HJ, Dougal K, Girdwood SE, Douglas JL, McEwan NR
In vitro analysis of the effect of supplementation with activated charcoal on the equine hindgut
J Equine Sci. 2016;27(2):49-55. doi: 10.1294/jes.27.49. Epub 2016 Jun 21

Activated charcoal - side effects

Giving activated charcoal may decrease absorption of medication from the gastrointestinal tract - in humans, giving activated charcoal is suggested for pergolide overdose - www.drugs.com - pergolide; metformin overdose - www.medcape.com - Toxicology of Oral Antidiabetic Medications; and phenylbutazone overdose - Position Statement and Practice Guidelines on the Use of Multi-Dose Activated Charcoal in the Treatment of Acute Poisoning. Note (in humans) activated charcoal does not absorb simple alcohols, strong acids or bases, common electrolytes, simple ions e.g. iron, lithium or cyanide - Manual of Emergency Medicine - G Richard Braen.

"Treatment of toxicity":
"Administering activated charcoal may reduce absorption of pergolide. In some human patients, charcoal has been more successful than emesis or lavage for pergolide overdosage." Pergolide - 2008 The United States Pharmacopeial Convention

www.drugs.com - Activated Charcoal Side Effects

Activated charcoal use in humans

Charcoal lemonade: Taking obsessive eating too far - Science Based Pharmacy May 2015

Chromium

According to Equine Applied and Clinical Nutrition (2013) p 223, whilst small amounts of chromium are essential for certain cell functions, chromium naturally occurring in the diet will ensure the required intake.

The NRC's Nutrient Requirements of Horses (2007) p 98 says that "no evidence has been found of a chromium deficiency in horses".

Can chromium help with EMS/laminitis?

Chromium is known to enhance the action of insulin, and appears to be involved in the metabolism of carbohydrate, fat and protein. Chromium has been found to correct glucose intolerance and insulin resistance in animals that were chromium deficient - but chromium deficiency is rare.

Equine Applied & Clinical Nutrition (2013) (p 223) suggests that chromium is being considered in the debate about insulin resistance and obesity, and that it is involved in the activation of glucose transporters, but says "the natural occurence of these elements" (chromium and boron) "will ensure the required intake." In the chapter on laminitis written by Geor and Harris, the section on chromium (p 482) concludes "Additional research is required to determine the efficacy of chromium supplements in the management of IR in horses."

Spears JW, Lloyd KE, Siciliano P, Pratt-Phillips S, Goertzen EW, McLeod SJ, Moore J, Krafka, K, Hyda J, Rounds W
Chromium propionate increases insulin sensitivity in horses following oral and intravenous carbohydrate administration
Journal of Animal Science published 25 March 2020, 1–11 doi:10.1093/jas/skaa095
48 3 to 8 year old Quarter Horses were assigned to 1 of 4 treatment groups: 0, 2, 4 or 8 mg of supplemented chromium (KemTRACE chromium) per day for 42 days, during which they were kept in individual stalls. 7 days prior to the study all horses were fed the control diet of 0.2 kg/100 kg bodyweight concentrate mix plus 1.75 to 2.0 kg/100 kg bodyweight grass hay, plus during the study 50 g of ground corn containing the 0, 2, 4 or 8 mg of chromium. Water was analysed for chromium and for 3 of 4 12 horse study periods had chromium levels below the limit of detection (0.100 mcg chromium/litre), and in 1 12 horse study contained 0.143 mcg chromium/litre.
The concentrate mix contained between 0.248 and 0.345 mg chromium/kg. The hay contained between 0.117 and 0.208 mg chromium/kg.
If the concentrate mix was fed at 1 kg and hay at 10 kg for a 500 kg horse, each of the 4 study periods would have supplied:
P1 1.492 mg, P2 1.897 mg, P3 2.328 mg and P4 1.985 mg chromium per horse per day before chromium supplementation. The paper reports that "based on feed intake over the entire study, the 2, 4 and 8 mg chromium/day treatments would have supplied 0.18, 0.36 and 0.74 mg chromium/kg of diet".
Blood was collected before and 2 and 4 hours after the morning concentrate meal (1 kg for a 500 kg horse) on days 0 and 28.
On day 42 a glucose tolerance test was carried out after horses had been fed limited hay and their 50 g corn and chromium supplement but no concentrate feed.
Results: All groups of horses gained weight: 0 mg Cr 4.42%, 2 mg Cr 3.51%, 4 mg Cr 3.36%, 8 mg Cr 3.66%.
Glucose results 0 mg Cr 2 mg Cr 4 mg Cr 8 mg Cr
Pre-study 81.4 82.1 77.5 81.3
Before concentrate feed 88.0 88.2 83.6 87.4
2 hours after feed 100.2 95.0 90.7 104.3
4 hours after feed 91.7 84.6 86.4 92.7
Insulin results
Pre-study 7.1 6.6 5.4 5.3
Before concentrate feed 10.8 10.6 9.2 9.2
2 hours after feed 21.3 20.0 19.4 24.5
4 hours after feed 18.0 13.1 13.8 19.0

Glucose and insulin concentrations were normal at all time points, suggesting that none of the horses had insulin dysregulation.
The authors suggest that the improved insulin sensitivity in horses fed 4 mg Cr/day suggests that the control diet had inadequate chromium to maximize insulin sensitivity.
The paper concludes that horses supplemented with 2 mg and 4 mg chromium per day had lower insulin concentrations following a concentrate meal than horses supplemented with 0 or 8 mg chromium. It should be noted that the horses used did not have insulin dysregulation, and that this was not a cross-over study (i.e. each horse was given one treatment only, not all 4 treatments).

Kellon EM
Ancillary Supplements for Horses with Laminitis and Metabolic Syndrome
Proceeding of the NO Laminitis! Conference Nov. 6 - 8, 2015 Austin, TX, USA
"Clinically insulin-resistant horses on an appropriate forage-based diet have not shown any positive effects from chromium supplementation."

According to the National Institutes of Health, data from 15 trials found that chromium supplementation had no effect on glucose or insulin concentrations in humans, apart from one trial which may have shown the benefits of supplementation in a chromium-deficient population.

Nutrition Therapy Recommendations for the Management of Adults With Diabetes written by Evert et al. for the American Diabetes Association and published in Diabetes Care November 2013 vol. 36 no. 11 3821-3842 found:
"There is no clear evidence of benefit from vitamin or mineral supplementation in people with diabetes who do not have underlying deficiencies."
"There is insufficient evidence to support the routine use of micronutrients such as chromium, magnesium, and vitamin D to improve glycemic control in people with diabetes."

The National Institutes of Health also suggest that certain medicines may interact with chromium, including corticosteroids, NSAIDs (e.g. Bute, Danilon) and Omeprazole (Gastroguard), and that niacin (vitamin B3) and insulin "may have their effects enhanced if taken together with chromium or they may increase chromium absorption".

Interestingly, diets where simple sugars provide more than 35% of calories have been found to increase chromium excretion in the urine, in humans.

Otabachian-Smith, Silvia
Dietary intake in a group of old mares fed a supplement containing long chain 18:3 (N-3) fatty acid and chromium
MSC Thesis Spring 2012

Diagnosis and Management of Horses with Equine Metabolic Syndrome (EMS)
Chameroy KA, PhD dissertation 2010
The section on chromium concluded: "It must still be determined whether chromium supplementation improves insulin sensitivity in insulin-resistant horses."
published as
Chameroy KA, Frank N, Elliott SB, Boston RC.
Effects of a supplement containing chromium and magnesium on morphometric measurements, resting glucose, insulin concentrations and insulin sensitivity in laminitic obese horses
Equine Vet J. 2011 Jul;43(4):494-9
6 obese horses with a history of laminitis and 1 obese horse with clinical laminitis were given a supplement containing 5 mg chromium as yeast (and magnesium and other nutraceuticals) for 16 weeks, during which time the horses were not exercised and their weight increased. Their insulin sensitivity was compared to controls (6 obese horses with a history of laminitis) at 0, 8 and 16 weeks. Resting insulin concentrations increased over time in both groups.
Conclusion: "The supplement containing chromium and magnesium evaluated in this study did not alter morphometric measurements, blood variables, resting insulin concentrations or insulin sensitivity in laminitic obese horses."

Vervuert I,  Oßwald B, Cuddeford D, Coenen M
Effects of chromium yeast supplementation on postprandial glycaemic and insulinaemic responses in insulin-resistant ponies and horses
Pferdeheilkunde vol. 26 (2010) 2 245-250
Restricted hay diets (1.2% of bodyweight) for 4 weeks with/without chromium supplementation and daily exercise led to weight loss and increased insulin sensitivity.
Chromium fed horses had a 32.8% decrease in post-starch meal insulin and a 48% decrease in resting insulin (to 33.2 uIU/ml, still above the normal range), with a 3.8% decrease in body weight, after the 4 week treatment period.
Control horses had a 23.7% decrease in post-starch meal insulin and a 66% decrease in resting insulin (to 14.4 uIU/ml - back within the normal range), with a 2.1% decrease in body weight, after the 4 week treatment period.
Interestingly the control group started with greater body condition scores (average 8.1 v 7.4 for the chromium fed group), but lost less weight than the chromium fed horses, but had the greatest improvement in resting insulin.

The paper concluded that body weight loss moderates insulin resistance. The authors suggest that chromium supplementation "seemed to have some potential in the treatment of IR in equids", but TLS doesn't agree that the figures support this, and it is notable that the authors failed to comment on the reduction in resting insulin being greater in the control group than the chromium fed group. They do however note "that the placebo horses had non-significant changes in resting and postprandial insulin profiles which were presumably linked to body weight loss" - they don't consider a 66% reduction in resting insulin significant?
The final conclusion:" Cr supplementation alone is an inadequate therapy and should always be associated with body weight loss due to restriction of energy intake and moderate exercise, key factors in the treatment of EMS." So in other words, as TLS recommends, treat EMS with a low energy (and low sugar/starch) diet if weight loss if necessary, and exercise when able.

Vervuert I, Cuddeford D, Coenen M
Effects of chromium supplementation on selected metabolic responses in resting and exercising horses
Equine and Comparative Exercise Physiology / Volume 3 / Issue 01 / February 2006, pp 19-27

Leptin in horses: Influences of body condition, gender, insulin insensitivity, feeding and dexamethasone
PhD dissertation JA Cartmill 2004
"chromium propionate supplementation at the dose and route of administration used herein was ineffective in reducing concentrations of insulin or leptin."

The effect of chromium supplementation on metabolic response to exercise in thoroughbred horses
Joe D Pagan, Stephen G Jackson and Stephen E Duren - Kentucky Equine Research Inc.
Trained horses exercised on a high speed treadmill responded to chromium supplementation but untrained, sedentary horses did not.

Sources of chromium
Brewer's yeast is often suggested as a good source of chromium - is it?
There appears to be chromium-rich and normal brewer's yeast.
Brewer's yeast is Saccharomyces cerevisiae, usually grown on hops or similar for use in the beer-making industry, after which is it harvested and killed. It is usually around 50% protein, and contains B vitamins and minerals.
Apparently brewer's yeast is bitter and some producers use a process to remove the bitterness, which also removes the chromium.

For chromium levels in the soil of England and Wales, see:
The advanced soil geochemical atlas of England and Wales - British Geological Survey

Chronic laminitis

See Chronic laminitis for explanation of changes in the feet following rotation/distal descent with photos.
Chronic laminitis refers to the displacement of the coffin/pedal bone (distal phalanx) within the hoof capsule, i.e. rotation or sinking.

After the Crash - Lessons from Chronic Laminitis - C Pollitt

Cinnamon

There have been suggestions that cinnamon may be of benefit to humans with type 2 diabetes and insulin resistance, but research findings are mixed and some recent reviews have found no or few health benefits for humans from eating cinnamon - see Wikipedia and below. Cinnamon is sometimes suggested as a supplement for horses with insulin dysregulation, but research in horses has found no improvements in insulin sensitivity. Several varieties of cinnamon are available commercially - Cassia cinnamon is the most common, less expensive, but contains coumarin which may cause liver damage and other side effects; Ceylon cinnamon is more expensive but considered safer.

Nutrition Therapy Recommendations for the Management of Adults With Diabetes written by Evert et al. for the American Diabetes Association and published in Diabetes Care November 2013 vol. 36 no. 11 3821-3842 found:
"There is insufficient evidence to support the use of cinnamon or other herbs/supplements for the treatment of diabetes."

Research supplementing mares with low insulin sensitivity with cinnamon showed no improvement in insulin sensitivity:

Earl LR, MSc thesis 2011
Intravenous injection of insulin for measuring insulin sensitivity in horses: effects of epinephrine, feeding regimen, and supplementation with cinnamon or fish oil
Published as:
Earl LR, Thompson DL, Mitcham PB
Factors Affecting the Glucose Response to Insulin Injection in Mares: Epinephrine, Short- and Long-Term Prior Feed Intake, Cinnamon Extract, and Omega-3 Fatty Acid Supplementation
Journal of Equine Veterinary Science Volume 32, Issue 1 , Pages 15-21, January 2012

EAAP 2006
‘Unusual’ feeds for performance horses
Harris PA, Gee HW

Owners of horses with insulin dysregulation should be aware that some research has found that cinnamon increases insulin, and understand that human diabetes (in which blood glucose levels become high and insulin low) is very different to Equine Metabolic Syndrome (in which blood glucose levels are usually normal and insulin high).

Cinnamon side effects and cautions (for humans)

Cassia Cinnamon - WebMD
Possibly effective for controlling blood sugar in humans with type 2 diabetes. In large amounts, may cause liver damage, may interfere with blood sugar control, may interfere with diabetes medication, may increase the risk of liver damage if taken with certain medications.

Ceylon Cinnamon - WebMD
Possibly ineffective for diabetes and obesity. Possibly unsafe when taken in larger amounts (than as a spice/flavouring). May interfere with blood pressure and blood sugar control. May interfere with diabetes medication.

Cinnamon - NCCAM
"Cassia cinnamon contains coumarin, the parent compound of warfarin, a medication used to keep blood from clotting. Due to concerns about the possible effects of coumarin, in 2006, the German Federal Institute for Risk Assessment warned against consuming large amounts of cassia cinnamon".

Brancheau D, Patel B, Zughaib M
Do Cinnamon Supplements Cause Acute Hepatitis?
Am J Case Rep, 2015; 16: 250-254 DOI: 10.12659/AJCR.892804
Coumarin in cinnamon is associated with acute liver damage - a metabolite of coumarin has been found to be hepatotoxic in animal studies. Giving cinnamon at the same time as prescribed drugs could increase the risk of significant liver damage.

6 Side Effects of Too Much Cinnamon - healthline.com 2019

CLIP - Corticotropin-like Intermediate Peptide

Corticotropin-like Intermediate Peptide (CLIP) is a POMC-derived peptide hormone that has not been well studied. CLIP has been shown to stimulate the release of insulin from pancreatic beta cells in rodents.

J Clin Invest. 1984; 74(5):1886–1889
Effect of corticotropin-like intermediate lobe peptide on pancreatic exocrine function in isolated rat pancreatic lobules
J B Marshall, L P Kapcala, L D Manning, A J McCullough

Brain Res Bull. 1991 Jan;26(1):99-111 (PubMed)
Immunohistochemical distribution of corticotropin-like intermediate lobe peptide (CLIP) immunoreactivity in the human brain
Zaphiropoulos A, Charnay Y, Vallet P, Constantinidis J, Bouras C
"The immunocytochemical distribution of CLIP (corticotropin-like intermediate lobe peptide) or ACTH(18-39), a small biologically active peptide, was examined in the human brain"..."The above neuroanatomical observations confirm and extend previous findings in animals, strengthening even more the possibility that this peptide may be involved in numerous behavioral, autonomic and physiological functions such as regulation of sleep-waking cycle, pain control and respiratory and cardiovascular regulation".

Cold weather

Cold weather seems to often be a trigger for laminitis for horses who have had laminitis before - there always appears to be an increase in laminitis flare-ups as soon as the weather turns cold (snow/ice) each winter. Several reasons have been suggested:

- circulation damage, or ongoing damage in the feet from rotation that hasn't been corrected making feet more sensitive to hard frozen ground,
- horses with PPID lose their ability to thermoregulate, therefore get more stressed by extreme temperatures, which could increase cortisol,
- hay soaking is not as effective at colder water temperatures,
- horses tend to get less exercise/turnout in cold/frosty/snowy weather,
- grass stores more sugar in sunny frosty weather.

When is dead grass safer to graze? Kathryn Watts www.safergrass.org
Factors affecting NSC levels in grass - Kathryn Watts www.safergrass.org

Things that can be done:
- keep feet warm and protected - use leg wraps/bandages, pads and boots on feet, warm deep bedding. Thick wool hiking socks can be great for keeping pony feet and legs warm!
- ensure feet are well trimmed/balanced - even the slightest tipping of the pedal bone onto the sole by high heels or pull on the laminae by long toes will exacerbate pain and discomfort when a horse is walking on hard rough ground.
- rug well, provide good shelter out of the wind/weather.
- soak hay in warm water .
- cut back feed if exercise/turnout is reduced.
- do not allow access to grass after a frost (following sunny weather) until there has been at least one night, ideally more, when the temperature stays above 5'C (this is when respiration takes place which uses up the stored sugar).
- provide warm water for drinking to reduce the risk of impaction colic (not such a great risk when soaking hay) - particularly for older/PPID horses that might have tooth problems.

Understanding and Managing Winter Laminitis - Dr Eleanor Kellon - www.holistichorse.com (Dec 2016)

Understanding Winter Laminitis - Dr Eleanor Kellon 2014 - Uckele

More about research into the circulation of blood in the feet of laminitic v non-laminitic ponies on www.hoofblog.com

The effect of cold weather on hormones:
Shiver T, Familari M, Aguilera G
Regulation of intermediate pituitary corticotropin-releasing hormone receptors by dopamine
Endocrinology. 1992 Apr;130(4):2299-304 (PubMed)
"The qualitatively similar and nonadditive effects of cold stress and dopaminergic agonists suggest that a dopaminergic mechanism may be involved in intermediate pituitary CRH receptor regulation during chronic cold stress."

Pääkkönen T, Leppäluoto J
Cold exposure and hormonal secretion: a review
Int J Circumpolar Health 2002; 61: 265-276 (the .pdf is available FOC online - search "health and performance in the cold workshop 2000 cold exposure and hormonal secretion").
In humans, ACTH was found to increase with short-term cold exposure; cortisol was found to increase with short and long-term cold exposure; insulin was found to increase with long-term cold exposure; and thyroid hormones were found to decrease with long-term cold exposure.

Combined Dexamethasone Suppression/TRH stimulation test

THIS TEST SHOULD NO LONGER BE USED TO DIAGNOSE PPID

J Vet Intern Med. 2006 Jul-Aug;20(4):987-93. (PubMed)
Evaluation of the combined dexamethasone suppression/ thyrotropin-releasing hormone stimulation test for detection of pars intermedia pituitary adenomas in horses.
Frank N, Andrews FM, Sommardahl CS, Eiler H, Rohrbach BW, Donnell RL
"The DEX/TRH test had sensitivity, specificity, positive predictive value, and negative (NPV) predictive value of 88, 76, 71, and 90%, respectively.
CONCLUSIONS AND CLINICAL IMPORTANCE: The combined DEX/TRH test was more sensitive than either of its component tests and had a high NPV, but was not as specific as the TRH component alone (92%). The DEX/TRH test should be used to screen older horses for PIPA."

However this test is no longer considered as useful as other tests. The PPID Working Group recommends resting ACTH, overnight DST, and TRH stimulation test with ACTH measured for equivocal/bordernline results.

Conferences

Future

Past

Australasian Equine Science Symposium (AESS) June 2018

2017 No Laminitis! Conference 27-29 October 2017, Tuscon, Arizona

Australasian Equine Science Symposium (AESS) Proceedings Vol 6 2016

2015 No Laminitis! Conference, 6 - 8 November 2015, Georgetown, Texas
Proceedings of the 2015 No Laminitis! Conference, 6-8 November 2015, Georgetown, Texas

Clinical Research Abstracts British Equine Veterinary Association Congress 2015 Volume 47 • Supplement 48 • September 2015

2015 14th International Congress of World Equine Veterinary Association - Guadalajara, Mexico - proceedings Equine Science Symposium, 26-29 May 2015, Florida
JEVS May 2015 Vol 35, 5, p 343-464 Proceedings of the 2015 Equine Science Society Symposium

2013 International Equine Conference on Laminitis and Diseases of the Foot, 1 - 3 November, Florida
JEVS October 2013 Vol 33, 10, p 763-884 - abstracts

2013 No Laminitis! Conference, 27 - 29 September 27 - 29 2013, Jacksonville, Oregon
Proceedings NO Laminitis! Conference 2013

2013 BEVA Congress 11-14 September, Manchester, UK

Journal of Equine Veterinary Science Volume 33, Issue 5, Pages A1-A6, 287-400 (May 2013)
Proceedings of the 2013 Equine Science Society Symposium, New Mexico

2013 ACVIM Forum June 12 – June 15, Seattle, WA

The Dr. Jack Walther 85th Annual Western Veterinary Conference February 17-21, 2013, Las Vegas, Nevada
EQ13 OLD SHAGGY HORSES: DIAGNOSIS OF PITUITARY PARS INTERMEDIA DYSFUNCTION (PPID) - Harold C. Schott II
EQ25 EVERY HOOF HAS A STORY: AN IN-DEPTH LOOK AT THE PHYSICAL EXAMINATION OF THE EQUINE HOOF - Debra R. Taylor
EX26 LAMINITIS REHABILITATION: IF THE CORIUM IS HAPPY, THERE IS HOPE - Debra R. Taylor EQ28 WHAT’S ALL THE HYPE ABOUT BAREFOOT HORSES? - Debra R. Taylor

AAEP 58th Annual Convention 1 - 5 December 2012, Anaheim, California

The Equine Limb: Advanced Diagnostics and Therapeutics 2 - 3 November 2012, Monterey, California
The focus will be on MRI, Regenerative Medicine and Updates on Laminitis.

AVEF 2012 40EMES JOURNEES ANUELLES 12 - 13 October 2012, Reims, France

BEVA Congress 2012, 12-15th September, Birmingham, UK
Saturday 15 September: Laminitis (Patricia Harris)
10.55 Relevance of clinical experimental models of laminitis - Raymond Geor
11.20 Diagnostic tests for a predisposition to laminitis - Nicola Menzies-Gow
11.45 Why are obese animals more prone to laminitis? - Raymond Geor
12.10 Nutrition and pasture associated laminitis - Patricia Harris
12.35 Discussion

Equine Endocrinology Summit, Sept 7-8 2012, Boston, Mass.
EMS, PPID Focus of Second Equine Endocrinology Summit - Erica Larson, News Editor - www.thehorse.com
September 27 2012, Article # 20693

Australasian Equine Science Symposium Vol. 4 13 - 15 June 2012, Gold Coast, QLD
Proceedings include:
Simon R Bailey - Equine Metabolic Syndrome: Causes and Consequences
N J Bamford, S J Potter, P A Harris, S R Bailey:
Effect of increasing adiposity, induced by a high fat low glycaemic diet or similar diet with once daily glucose, on insulin sensitivity in horses and ponies
In vivo apparent feed digestibility measurements in ponies, standardbreds and andalusian cross horses.
Insulinaemic responses to oral glucose in standardbreds, ponies and andalusian-cross horses.

2012 ACVIM Forum 30 May - 02 June New Orleans

European Equine Endocrinology Symposium 30 - 31 March 2012, Berlin
Andy Durham - PPID Diagnostic Review

84th Annual Western Veterinary Conference 19-23 February 2012
Obesity & Insulin Resistance in Horses: Implications for Health - P Johnson
Obesity & Insulin Resistance in Horses: Management & Prevention - P Johnson
Equine Cushing's Disease (PPID): Pathophysiology & Clinical Recognition - P Johnson
Equine Cushing's Disease (PPID): Diagnostic Corroboration & Treatment - P Johnson
Nutritional Management of Obesity in Horses - R Geor
Nutrition and Exercise for Management of Laminitis-Prone Equids - R Geor

AAEP 57th Annual Convention San Antonio, Texas November 18-22, 2011

The Laminitis Conference - 29-31 Oct 2011, Florida
Summary of the Proceedings by Dr Rob Boswell

FAEP 49th Annual Ocala Equine Conference - 21-24 Oct 2011, Florida
Endocrinopathic laminitis - Nicholas Frank
Equine Metabolic Syndrome: Diagnosis and Treatment - Nicholas Frank
Pituitary Pars Intermedia Dysfunction: Diagnosis and Treatment - Nicholas Frank

50th BEVA Congress 7-10 September 2011, Liverpool
Managing weight loss in the hyperinsulinaemic pony - A Dugdale
The role of hyperinsulinaemia in the development of laminitis - C McGowan
Inter-relationships of hyperinsulinaemia and PPID - A Durham
How to diagnose: Cushing's disease/metabolic syndrome - A Durham
Adrenocorticotropic hormone in domestic donkeys - reference values, seasonality and association with laminitis - N du Toit et al
Frequency and speculated causes of equine laminitis in Great Britain - CE Wylie et al

Proceedings of the 2011 Equine Society Symposium
Journal of Equine Veterinary Science Volume 31, Issues 5–6, Pages A1-A10, 203-356 (May–June 2011)

Boehringer Ingelheim 2011 Equine Endocrinology Summit

5th International Conference on Laminitis and Diseases of the Foot, 17-18 Sept 2010, Monterey, Ca
The Fight to Conquer Laminitis - Tracy Gantz The Horse.com

Coronary band separation

Journal of Equine Veterinary Science Article in Press Oct 2011
A Retrospective Study of 23 Cases of Coronary Band Separation Longer than 8 cm as a Sequel to Severe Laminitis
Eustace RA, Emery SL, Cripps PJ

Corticosteriods

Corticosteroid medicines - steroid hormone medicines with names usually ending in -one (e.g. dexamethasone, triamcinolone, prednisolone) - increase insulin dysregulation and the risk of laminitis, even in healthy, fit horses.

Corticosteroids include glucocorticoids, mineralocorticoids and sex hormones, and it is glucocorticoids that concern us in terms of laminitis risk, but they are usually referred to simply as corticosteroids. Glucocorticoids bind to glucocorticoid receptors which are found on almost every mammal cell, and are used to reduce immune system response including inflammation. Glucocorticoids are produced naturally in the adrenal glands and affect glucose metabolism - cortisol is a glucocorticoid.

AAVPT monograph - Corticosteriods

Myths and Truths About Controlling Pain and Inflammation in Horses
A major concern with administration of corticosteroids to horses is the risk of inducing laminitis (founder). This occurs sporadically and can not be scientifically demonstrated with all corticosteroid products. However, the consequences of laminitis can be so devastating, that it is a consideration with administration of any corticosteroid product to horses. Scientific studies have shown that corticosteroids can cause constriction of arteries of the feet of normal horses. In another study, high doses of corticosteroids alone did not induce laminitis. But when the same horses were fed carbohydrate overload diets after corticosteroid treatment, the resulting laminitis was more severe than in horses that did not receive corticosteroids.

Bailey SR
Corticosteroid-associated laminitis
Vet Clin North Am Equine Pract. 2010 Aug;26(2):277-85

Data sheets for common corticosteroids
Depo-Medrone V (Methylprednisolone Acetate 4.0% w/v) "The product is contra-indicated for the treatment of laminitis in horses. Additionally it should be noted that use of the product in horses for other conditions could induce laminitis and careful observations during the treatment period should be made." NOAH Compendium.

Dexadreson (dexamethasone 2 mg/ml) "Care should be taken when the product is used for the treatment of laminitis in horses, where there is the possibility that such treatment could worsen the condition. The use of the product in horses for other conditions could induce laminitis and careful observation during the treatment period should be made." NOAH Compendium.

Dexafort (dexamethasone) Advice as for Dexadreson.

Rapidexon (dexamethasone 2 mg/ml) "Use of corticosteroids in horses has been reported to induce laminitis. Therefore horses treated with such preparations should be monitored frequently during the treatment period." NOAH Compendium.

Voren (dexamethasone 1 mg/ml) "The product is contra-indicated for the treatment of "laminitis" in horses, where there is the possibility that such treatment could worsen the condition. Additionally it should be noted that use of the product in horses for other conditions could induce laminitis and careful observations during the treatment period should be made." NOAH Compendium.

Does corticosteriod (glucocorticoid) administration induce/increase the risk of inducing laminitis?

Yes.

Casareño, a 16 year old Andalusian (PRE), developed laminitis in all four feet in May 2014, five days after having a single corticosteroid injection (6 mg Celestone - betamethasone) for a suspected pastern joint sprain. He had had no problems with laminitis before the corticosteroid injection, and has had none since his recovery (as at November 2020). See Casareño's recovery.

Front foot several months after low-dose corticosteroid treatment

A 3 year old Lusitano developed laminitis in all 4 feet on day 15 of a month’s course of low-dose corticosteriod injections for a minor lung infection. A significant hoof ring was seen on all 4 feet several weeks after the laminitis. Although not tested, he is now assumed to be insulin resistant and managed accordingly.

Hind foot several months after low-dose corticosteroid treatment

Corticosteroids cause insulin resistance, and are often used to induce insulin resistance in research. Insulin resistance can cause hyperinsulinaemia, hyperinsulinaemia is thought to be the cause of endocrinopathic laminitis. So it follows that corticosteroids can increase the risk of endocrinopathic laminitis.

Smith LCR
What is Known About the Safety of Intraarticular Corticosteroid Injections and How Might This Impact Safety in Thoroughbred Racehorses?
JEVS October 2018 Volume 69, Pages 21–28
"In conclusion, practitioners should be aware that the use of intraarticular corticosteroids may be associated with negative consequences."

Knowles E
Glucocorticoids and laminitis: a real risk?
UK Vet - Equine Sept 2018 DOI: 10.12968/ukve.2018.2.5.140

Coleman MC, Belknap JK, Eades SC, Galantino-Homer HL, Hunt RJ, Geor RJ, McCue ME, McIlwraith CW, Moore RM, Peroni JF, Townsend HG, White NA, Cummings KJ, Ivanek-Miojevic R, Cohen ND
Case-control study of risk factors for pasture-and endocrinopathy-associated laminitis in North American horses
J Am Vet Med Assoc. 2018 Aug 15;253(4):470-478. doi: 10.2460/javma.253.4.470
Risk factors for endocrinopathic laminitis included having received corticosteroids within 30 days (with the caveat that the study included a low number of cases and controls that had received corticosteroids).

Knowles EJ
What is the risk that corticosteroid treatment will cause laminitis?
Equine Veterinary Education published online 22 February 2018. https://doi.org/10.1111/eve.12901

Rendle DI, Rutledge F, Hughes KJ, Heller J, Durham AE
Effects of metformin hydrochloride on blood glucose and insulin responses to oral dextrose in horses
Equine Vet J. 2013 Nov;45(6):751-754
7 healthy geldings aged 5 to 19 years with BCS 3/9 to 6/9 were given 0.08 mg dexamethasone per kg bodyweight intravenously every other day for a total of 9 doses (so 40 mg dexamethasone per 500 kg horse x 9 over 17 days) "to induce insulin resistance". Oral glucose test results showed that "administration of dexamethasone had significant effects ... indicating that reductions in tissue sensitivity to insulin had been induced."

Tóth F, Frank N, Geor RJ, Boston RC
Effects of pretreatment with dexamethasone or levothyroxine sodium on endotoxin-induced alterations in glucose and insulin dynamics in horses
Am J Vet Res. 2010 Jan;71(1):60-8
24 horses received 200 g of oats plus either 48 mg of levothyroxine, 20 mg of dexamethasone, or nothing (control) for 15 days and were housed in individual stalls. Insulin sensitivity decreased in all groups, with the largest decrease in insulin sensitivity in the dexamethasone group. All horses were then given lipopolysaccharide (endotoxemia) (20 ng/kg) - this further decreased mean insulin sensitivity by 71% in the dexamethasone group, 63% in the control group, but did not decrease mean insulin sensitivity further in the levothyroxine group.
"Conclusions and clinical relevance: Insulin sensitivity decreased during the pretreatment period in all 3 groups, indicating that hospitalization " (box rest) "affected glucose and insulin dynamics. Dexamethasone significantly lowered SI, and endotoxemia further exacerbated insulin resistance. In contrast, there was no additional effect of endotoxemia on SI in horses pretreated with levothyroxine, suggesting that this treatment prevented endotoxemia-induced insulin resistance."

Tiley HA, Geor RJ, McCutcheon LJ
Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses
Am J Vet Res. 2007 Jul;68(7):753-9. (PubMed)
6 healthy Standardbreds received 0.08 mg/kg IV dexamethasone every 48 hours during a 21 day period. Mean insulin concentration was significantly higher in dexamethasone-treated horses than control horses on days 7, 14, and 21, and insulin sensitivity decreased significantly in dexamethasone-treated horses.
Conclusions: "The study revealed marked insulin resistance in healthy horses after 21 days of dexamethasone administration. Because insulin resistance has been associated with a predisposition to laminitis, a glucocorticoid-induced decrease in insulin sensitivity may increase risk for development of laminitis in some horses and ponies."

See also:
Tiley HA MSc thesis 2006 (University of Guelph)
Skeletal muscle glucose metabolism in a dexamethasone model of insulin resistance in standardbred horses

J vet Pharmacol. Therap. 23, 287-292. 2000
Pharmacokinetics and metabolic effects of triamcinolone acetonide and their possible relationships to glucocorticoid-induced laminitis in horses
French K, Pollitt C, Pass M
"Glucocorticoids such as triamcinolone are known to precipitate laminitis (Lawrence et al. 1985; Kelley 1997)".
A single dose of 0.2 mg/kg triamcinolone acetonide (TMC) (100 mg/500 kg horse) was given to 5 presumably healthy horses, aged 6 to 14 years, kept in stables during the study period. Giving 0.2 mg/kg triamcinolone by both IV and IM administration caused significant increases in blood glucose and insulin, and although overt clinical laminitis did not occur, laminar rings developed in the hooves of 4/5 horses. After IM administration, appetite and thirst appeared to be reduced for 3-4 days.
Following IV administration, blood glucose levels had increased significantly after 5 hours, peaking at around 24 hours, and returning to normal after around 3 days, and blood insulin had increased significantly after 12 hours, peaking around 24 hours and returning to normal after around 3 days.
IM administration caused greater and longer lasting increases in blood glucose and insulin than IV administration, with a significant increase in blood glucose by 24 hours, peaking at around 36 hours and returning to normal after around 8 days, and serum insulin showing a significant increase by 24 hours, peaking at 6 days and declining back towards normal levels by around 8 days. Following IM administration of triamcinolone, serum triglycerides also increased significantly after 4 days, peaking at around 8 days and returning to normal levels around 14 days after a single injection.
3 mares aged 9 to 14 years were also given a single dose of 0.05 mg/kg TMC (25 mg/500 kg - the maximum normal dose) by intra-musclar administration. Blood glucose increased significantly by around 24 hours, peaked at around 36 hours and remained above normal for around 4 days. insulin was not reported.

Seung-ho Ryu, Byung-sun Kim, Chang-woo Lee, Junghee Yoon, Yonghoon Lyon Lee
Glucocorticoid-induced laminitis with hepatopathy in a Thoroughbred filly
J. Vet. Sci. (2004),5(3), 271–274
Repeated administration of exogenous corticosteroid (20 mg of triamcinolone acetonide given intra-muscularly for 10 days (200 mg in total)) for a lameness were considered most likely to have induced laminitis and hepatopathy in a 3 year old Thoroughbred filly. 25 days after the start of corticosteroid treatment she had hematuria (blood in urine), loss of appetite, weight loss, depression, hyperemia, flare in the bladder wall, neutrophilia, lymphopenia, polyuria and polydipsia. Increased AST, GGT and total bilirubin indicated hepatophathy (liver damage). Signs of laminitis developed in both front feet around 30 days after the first corticosteroids were given; at this point lateromedial radiographs showed significant rotation. NSAIDs and ACP failed to alleviate clinical signs, and approximately one month later further radiographs showed that both front P3s had penetrated the soles.

Laminitis and steroids– a connection? Stephen E. O'Grady, DVM, MRCVS

Donaldson et al. 2004 - of 40 horses examined because of laminitis, 2 horses had laminitis associated with dexamethasone administration for recurrent airway obstruction (no further details).

Cohen ND, Carter GK
Steroid hepatopathy in a horse with glucocorticoid-induced hyperadrenocorticism
J Am Vet Med Assoc 1992 Jun 1;200(11):1682-4
"Steroid hepatopathy was diagnosed in a horse with glucorticoid-induced hyperadrenocorticism on the basis of anamnesis, serum biochemical data, and histologic findings of hepatic biopsy. Initially, clinical signs of polyuria, polydypsia, and muscular degeneration were seen. The horse developed laminitis during hospitalization."

Do corticosteroids cause laminitis? See discussion on forum..

Do you know a horse that developed laminitis or had laminitis that appeared to worsen after being given corticosteroids, e.g. dexamethasone? If so, please contribute your experience on The Laminitis Site forum.

What about intra-articular injections - is there still a risk of laminitis?

Yes - corticosteroids injected into a joint will have a systemic effect:

In the successful prosecution of two vets for the death of dressage horse Annastasia, owned by Jane McGarel-Groves, in 2001, the court accepted that an overdose of corticosteroids and triamcinolone cause the laminitis from which Anna died in July, having had 80 mg triamcinolone injected into each of her hocks and 20 mg dexamethasone into her back in May. Anna started to show signs of laminitis 11 days after having the corticosteroid injections. Vets Erik Grandiere and Philip Glyn were sued a total of £350,000.
See: Owner wins £350,000 damages from vets - Horse & House July 2005 and below.

Dutton H
The corticosteroid laminitis story: 1: Duty of care
Equine Vet J. 2007 Jan;39(1):5-6 (Full paper: DeepDyve)
Dressage horse Annastasia was on track to compete at the 2000 Sydney Olympics. However she developed orthopaedic problems in 1997, and in 1999 showed signs of being uneven and was given corticosteroid injections in the hocks and back by a French vet. Anna had a good year but then her performance dipped and in May 2001 her 1999 corticosteroid treatment was repeated by a French national team vet with her usual British vet present - both of Anna's hocks were injected with 80 mg triamcinolone and her back was injected with 20 mg dexamethasone. Anna developed laminitis and died in July 2001. In court "it was accepted that an overdose of corticosteroids and triamcinolone caused the laminitis from which Anna died". The observing British vet was found guilty, as well as the French vet who gave the corticosteroids and admitted his errors in administering the treatment. The British vet said that he would not have administered such a high dose, and that had the French vet told him he was going to do so he "would have commented that it was a high dose...with such an exceptionally high dose you would have to ...point out the risk of laminitis".

Bailey SR, Elliott J
The corticosteroid laminitis story: 2. Science of if, when and how
Equine Vet J 2007 Jan;39(1):7-11. doi: 10.2746/042516407x166035 (Full paper: DeepDyve)

Bathe AP
The corticosteroid laminitis story: 3. The clinician's viewpoint
Equine Vet J . 2007 Jan;39(1):12-3. doi: 10.2746/042516407x165801 (Full paper: DeepDyve)

Mora Pereira M, Groover E, Wooldridge A, Caldwell F
Review of glucocorticoid therapy in horses. Part 2: Clinical use of systemic glucocorticoids in horses
Equine Veterinary Education Volume 30, Issue 4 April 2018 Pages 213-224 (DeepDyve)

Cuming RS, Groover ES, Wooldridge AA. Caldwell FJ
Review of glucocorticoid therapy in horses. Part 1: Pharmacology
Equine Veterinary Education Volume 30, Issue 3 March 2018 Pages 141-150 (DeepDyve)

Capolongo F, Gallina G, Fidani M, Baia F, Montessissa C
Endocrine evaluation after an intra-articular therapeutic dosage of dexamethasone in horses
Journal of Veterinary Pharmacology and Therapeutics Article first published online: 1 APR 2013

Cornelisse CJ, Robinson NE
Glucocorticoid therapy and the risk of equine laminitis
Equine Veterinary Education Vol 25, Issue1 p 39-46 January 2013

50th BEVA Congress 2011
Practical corticosteroid use
Andrew P Bathe - Rossdales Equine Hospital
"Because of the risk of laminitis I would normally use a maximum dose of 20 mg of triamcinolone in a sports horse. Racing thoroughbreds seem more resistant to developing laminitis and a dose of up to 40 mg would commonly be used in our practice."
"In a retrospective study in our practice, only 3 horses out of 2000 receiving joint injections developed signs of laminitis and 2 of these were transient bouts in ponies which had previously had laminitis. Thus the owners must be warned of the risk of laminitis, albeit a very low risk if the products are used appropriately."

Equine Veterinary Education (2004) Volume: 16, Issue: 2, Pages: 86-89
Clinical use of triamcinolone acetonide in the horse (205 cases) and the incidence of glucocorticoid-induced laminitis associated with its use
McCluskey M, Kavenagh P
In a retrospective study of the use of triamcinolone acetonide in 205 horses (mostly thoroughbreds/TB crosses and Standardbreds), only 1 was diagnosed with laminitis after treatment - a 7 year old thoroughbred gelding was diagnosed with laminitis one week after treatment with 40 mg intra-articular TMC for osteoarthritis (the horse had been diagnosed with laminitis 7 months previously).

Cortisol

Cortisol and PPID, ID and EMS

Vaughn SA, Norton NA, Hart KA
Circulating hypothalamic-pituitary-adrenal axis hormones and insulin concentrations in horses and ponies
Journal of Equine Veterinary Science published online 14 November 2021, 103810. https://doi.org/10.1016/j.jevs.2021.103810
Insulin concentration differs between healthy ponies and horses
Free cortisol fraction differs between insulin dysregulated ponies and horses
Total cortisol concentration does not differ between healthy ponies and horses

Morgan RA, Keen JA, Homer N, Nixon M, McKinnon-Garvin A, Moses-Williams J, Davis S, Hadoke PWF, Walker BR
Dysregulation of cortisol metabolism in equine pituitary pars intermedia dysfunction
Endocrinology. 2018 Oct 4. doi: 10.1210/en.2018-00726. [Epub ahead of print]

Hofberger SC, Gauff F, Thaller D, Morgan R, Keen JA, Licka TF
Assessment of tissue-specific cortisol activity with regard to degeneration of the suspensory ligaments in horses with pituitary pars intermedia dysfunction
Am J Vet Res. 2018 Feb;79(2):199-210. doi: 10.2460/ajvr.79.2.199
"Horses with PPID had evidence of SL (suspensory ligament) degeneration with significantly increased proteoglycan accumulation. Neck skin tissue was found to be significantly thinner in PPID-affected horses than in young control horses.
CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that tissue-specific dysregulation of cortisol metabolism may contribute to the SL degeneration associated with PPID in horses."

Hart KA, Vaughn S, Norton NA
The Effect of Insulin Dysregulation and Breed on HPA Axis Function and Plasma Cortisol Binding Dynamics in Ponies and Horses
International Equine Endocrine Summit Jan 2017

Hart KA, Kitchings KM, Kimura S, Norton NA, Myrna KE
Measurement of cortisol concentration in the tears of horses and ponies with pituitary pars intermedia dysfunction
Am J Vet Res. 2016 Nov;77(11):1236-1244
Tear and serum cortisol concentrations were compared between horses and ponies with PPID and healthy horses and ponies 15 or younger and 20 or older. "Median tear cortisol concentration was significantly higher in PPID animals than in aged control animals, despite comparable serum cortisol concentrations in PPID and aged control animals. Median tear-to-serum cortisol concentration ratios were also significantly higher in PPID animals than in aged control animals. Serum and tear cortisol concentrations were not significantly correlated in PPID or control animals. CONCLUSIONS AND CLINICAL RELEVANCE Some horses and ponies with PPID had increased tear cortisol concentrations, compared with concentrations in healthy aged animals. Localized cortisol production in the tear film or altered cortisol binding dynamics could have contributed to this increase. Further studies are warranted to evaluate these mechanisms and to determine whether increased tear cortisol concentrations are associated with delays in corneal wound healing in horses and ponies with and without PPID."

Hart KA, Wochele DM, Norton NA, McFarlane D, Wooldridge AA, Frank N
Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses
J Vet Intern Med. 2016 Mar-Apr;30(2):653-63. doi: 10.1111/jvim.13839. Epub 2016 Feb 9

Measuring cortisol

Measuring blood plasma cortisol is the standard for measuring stress in animals. However, the blood sampling process itself may cause stress, therefore measuring corticosteroids in saliva, urine and feces has also been investigated.
Measuring cortisol is difficult because "corticosteroid hormone secretion is usually pulsatile, follows diurnal and seasonal rhythms, is influenced by feed intake and environmental factors such as temperature and humidity, age and physiological state", and large differences are seen between species, breeds and individuals, due to genetic and environmental factors.

Normal reference ranges for cortisol:
Rossdales serum cortisol 71-240 nmol/l (for adult non-Thoroughbred horses)

Mormède P1, Andanson S, Aupérin B, Beerda B, Guémené D, Malmkvist J, Manteca X, Manteuffel G, Prunet P, van Reenen CG, Richard S, Veissier I
Exploration of the hypothalamic-pituitary-adrenal function as a tool to evaluate animal welfare
Physiol Behav. 2007 Oct 22;92(3):317-39. Epub 2007 Jan 16

Salivary cortisol concentration measurements may be as accurate as serum (blood) cortisol concentration measurements:

Peeters M, Sulon J, Beckers JF, Ledoux D, Vandenheede M
Comparison between blood serum and salivary cortisol concentrations in horses using an adrenocorticotropic hormone challenge
Equine Vet J. 2011 Jul;43(4):487-93. doi: 10.1111/j.2042-3306.2010.00294.x. Epub 2010 Sep 29
Conclusion: "The reliability of both RIAs and regression found between serum and salivary cortisol concentrations permits the validation of saliva-sampling as a noninvasive technique for cortisol level assessment in horses."

Pawluski J, Jego P, Henry S, Bruchet A, Palme R, Coste C, Hausberger M
Low plasma cortisol and fecal cortisol metabolite measures as indicators of compromised welfare in domestic horses (Equus caballus)
PLoS ONE 2017 12(9): e0182257. https://doi.org/10.1371/journal.pone.0182257
"we show that plasma cortisol and FCM measures are correlated"

Fecal cortisol metabolites (FCM) may be correlated to plasma cortisol.
A clear positive relationship was shown between evening plasma cortisol levels and fecal cortisol metabolite levels. However, FCM levels reflect an average level of circulating glucocorticoids during a time window with a species specific delay time, and therefore plasma cortisol levels may be advantageous in certain situations as they provide more direct measures of total cortisol levels at a given time point.
Pawluski J, Jego P, Henry S, Bruchet A, Palme R, Coste C, et al. (2017)
Low plasma cortisol and fecal cortisol metabolite measures as indicators of compromised welfare in domestic horses (Equus caballus)
PLoS ONE 12(9): e0182257. https://doi.org/10.1371/journal. pone.0182257

Is total cortisol an accurate measurement of the HPA axis?

Alexander SL, Irvine CH
The effect of social stress on adrenal axis activity in horses: the importance of monitoring corticosteroid-binding globulin capacity
J Endocrinol June 1, 1998 157 425-432

This research concluded that the binding capacity of corticosteroid-binding globulin and free cortisol concentrations should be measured as well as total cortisol levels to accurately asses adrenal axis status in horses.

Do horses have a circadian rhythm for cortisol?

Hart KA, Dirikolu L, Ferguson DC, Norton NA, Barton MH
Daily endogenous cortisol production and hydrocortisone pharmacokinetics in adult horses and neonatal foals
Am J Vet Res. 2012 Jan;73(1):68-75. doi: 10.2460/ajvr.73.1.68

Irvine CH, Alexander SL
Factors affecting the circadian rhythm in plasma cortisol concentrations in the horse
Domest Anim Endocrinol. 1994 Apr;11(2):227-38
"A circadian rhythm in plasma cortisol concentrations has been reported in some but not all studies."
"These observations highlight the difficulties in determining the cortisol status of a horse, since measurements will be affected by time of day, the occurrence of short-term fluctuations, and how accustomed the horse is to its environment."

Noble GK, Sillence MN
Diurnal rhythm and effects of feeding, exercise and recombinant equine growth hormone on serum insulin concentrations in the horse
Equine Veterinary Journal online Jan 2013
Non-exercised, healthy geldings showed a circadian rhythm for cortisol concentrations, with a nadir (lowest point) at midnight (49.2 +/- 13.6 nmol/l) and a zenith (peak) at 7.30 am (just before being fed, 15.5 hrs after previous feeding, and just as it became light - 144.2 +/- 27.2 nmol/l).

Morgan R, Hadoke P, Walker B, Keen J
Abnormal glucocorticoid metabolism in horses with metabolic syndrome
Endocrine Abstracts (2014) 34 P208 DOI:10.1530/endoabs.34.P208
Obese horses with EMS were found to have increased urinary cortisol clearance but plasma cortisol was no greater than controls. EMS horses had increased cortisol regeneration in adipose tissue by 11β-HSD1 (up-regulated 11β-HSD1 mRNA in perirenal and linea alba adipose tissue, but not in neck crest adipose tissue or the liver).

See also: Research update: steroids and laminitis - The Royal Dick School of Veterinary Studies Spring Newsletter 2013
As at Spring 2013 Ruth Morgan had found that steroid levels appeared to be excessively high in fat tissues of horses with EMS, and that horse blood vessels proliferate excessively when exposed to steroids (in humans and mice, blood vessels stop growing when exposed to steroids). This raises interesting questions about how steroids affect the blood vessels in horses' feet (remember Melody de Laat found suggestion of vasodilation when hyperinsulinaemic laminitis was induced), affect wound healing and ovulation.

Cordero M, Brorsen BW, McFarlane D
Circadian and circannual rhythms of cortisol, ACTH, and α-melanocyte-stimulating hormone in healthy horses
Domest Anim Endocrinol. 2012 Nov;43(4):317-24
"Serum cortisol concentrations (P < 0.01) ... showed a significant circadian periodicity in horses. An effect of season on hormone concentration was observed with plasma ... cortisol concentration greater in the spring (P < 0.001). Age did not affect cortisol rhythm, but it did blunt the variation in cortisol concentration in horses, similar to what has been previously reported to occur in aged people and dogs. In addition, our results suggest that clinically and diagnostically normal, non-PPID-affected horses commonly have a loss of cortisol diurnal rhythm. Therefore, measurement of circadian rhythm is not an appropriate diagnostic test for PPID."

J Vet Pharmacol Ther. 2012 Sep 3
Short-term incubation of equine laminar veins with cortisol and insulin alters contractility in vitro: possible implications for the pathogenesis of equine laminitis
Keen JA, McGorum BC, Hillier C, Nally JE
This study investigated the effects of cortisol and insulin, hormones that affect both glycaemic status and vascular function, on the in vitro contractility of isolated healthy equine small laminar veins. Small veins (150-500 μm) draining the digital laminae from healthy horses or ponies were investigated by wire myography. Concentration response curves were constructed for noradrenaline (NA), phenylephrine (PE), endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT) in the presence of either cortisol (10(-6 ) m) or insulin (1000 μIU/mL). Cortisol significantly increased the maximum contractility of laminar veins to the vasoconstrictors NA and 5-HT but decreased the maximal contraction to ET-1. Insulin decreased the contractility of vessels to PE and ET-1. It is possible that short-term cortisol excess could enhance venoconstrictor responses to 5-HT and NA in laminar veins in vivo, thereby predisposing to laminitis. Additionally, a reduction in the ability of insulin to counteract alpha-adrenoreceptor and ET-1-mediated contraction, likely to occur in subjects with insulin resistance, may further exacerbate venoconstriction in animals prone to laminitis. These mechanisms may also predispose horses with disorders such as equine Cushing's disease and equine metabolic syndrome to laminitis.

Söder J, Bröjer JT, Nostell KEA
Interday variation and effect of transportation on indirect blood pressure measurements, plasma endothelin-1 and serum cortisol in Standardbred and Icelandic horses
Acta Veterinaria Scandinavica 2012, 54:37 (Full)
Notes from full paper:
Serum cortisol concentrations (hydrocortisone Compound F) were measured with a radioimmunoassay kit (Coat-A-Count Cortisol, Siemens). Intra-assay CV for serum cortisol was 5.7%. Serum cortisol showed an acceptable interday variation.
An hour-long journey by trailer to new stables did not significantly affect the mean serum cortisol concentration measured at least 12 hours after arrival. This is in contrast to earlier research which found higher serum cortisol levels in horses after transportation (when measured on the day of travel) compared to horses that hadn't been transported. Research by Forhead et al. 1995 found that cortisol concentrations increased in donkeys after travelling but the circadian rhythm was reestablished 8.5 - 10.5 hours later.
"In horses, cortisol production has a circadian rhythm with peak levels in the early morning and a nadir at night [12,29]." Therefore cortisol results are influenced by sampling time. The circadian rhythm can be easily disturbed, e.g by fasting and stress.
The Icelandic horses had significantly lower serum cortisol concentrations than the Standardbred horses (and higher ET-1 concentrations but there was no difference in blood pressure between the breeds). Diet and fitness status were not considered to explain this difference. "Chronic inflammation is known to depress cortisol concentrations in horses [32] and systemic inflammation is an important component of EMS [33]. The lower mean cortisol concentrations shown in the Icelandic horses in the present study could be related to breed differences, partial IR or be management dependent." "Previous studies have found that laminitis prone ponies have a different metabolic profile compared to non-laminitic ponies with significantly higher BCS, plasma insulin concentrations as well as decreased cortisol concentrations [4,35]."

Johnson PJ, Ganjam VK, Slight SH, Kreeger JM, Messer NT
Tissue-specific dysregulation of cortisol metabolism in equine laminitis
Equine Vet J. 2004 Jan;36(1):41-5
Skin and hoof lamellar samples were obtained from 10 normal horses and 10 horses before and after the induction of sepsis-related (grain overload) laminitis, and hoof lamellar samples also obtained from 4 horses with chronic laminitis (cause/type of laminitis not mentioned), and activity of 11beta-HSD-1 (steroid converting enzyme 11beta-hydroxysteroid dehydrogenase-1 regulates local tissue activity of glucocorticoids) and 11-ketoreductase determined.
11-ketoreductase activity exceeded 11beta-dehydrogenase activity in skin and lamellar tissues.
Skin 11beta-HSD-1 activity was higher than lamellar 11beta-HSD-1 activity in all groups.
Following induction of sepsis-related laminitis, skin 11beta-HSD-1 activity increased by 227% and 11-ketoreductase by 220%, and lamellar 11beta-HSD-1 activity increased by 173% and 11-ketoreductase by 398%.
Conclusion: "The 11-ketoreductase moiety of 11beta-HSD-1 plays a role in equine skin and hoof lamellae regarding the regulation of local glucocorticoid activity. Increased 11-ketoreductase activity will lead to increased local tissue glucocorticoid activity by virtue of conversion of cortisone to cortisol."

Toutain PL, Oukessou M, Autefage A, Alvinerie M
Diurnal and episodic variations of plasma hydrocortisone concentrations in horses
Domest Anim Endocrinol. 1988 Jan;5(1):55-9
"Both circadian and episodic variation was observed. The mean plasma hydrocortisone concentration was a maximum of 58.8 +/- 9.54 ng/ml at 9.19 +/- 0.59 hr and a minimum of 27.85 +/- 6.85 g/ml at 21.19 +/- 0.59 hr. The number of episodes of secretion was 10.0 +/- 1.41."

The Journal of Nutrition 1987
Responses of Blood Glucose, Insulin and Cortisol Concentrations to Common Equine Diets
Stull C, Rodiek A
found that cortisol levels exhibit a circadian rhythm, with elevated values found in the morning and low values in the evening.

C-peptide

C-peptide (connecting peptide) is secreted concurrently with insulin by the pancreas - proinsulin is cleaved (divided) in the beta-cells of the pancreas to form insulin and C-peptide, and these are released in equimolar amounts into the portal circulation. C-peptide is cleared by the kidney and not by the liver and has a half-life of 20 - 30 minutes (in humans), compared to insulin which is mostly cleared by the liver and has a half-life of 3 - 5 minutes. The difference between insulin and C-peptide can be calculated and used to assess insulin secretion and insulin clearance by the liver.

A human RIA can be used to measure C-peptide in equine serum.

de Laat MA, van Haeften JJ, Sillence MN.
The effect of oral and intravenous dextrose on C-peptide secretion in ponies.
J Anim Sci. 2016 Feb;94(2):574-80. doi: 10.2527/jas.2015-9817. PMID: 27065127.
Ponies, either hyperinsulinaemic or normoinsulinaemic, were given oral and IV dextrose after fasting. C-peptide concentrations increased rapidly from fasted levels after both oral and IV dextrose. The area under the curve was similar in hyperinsulinaemic and normoinsulinaemic ponies after IV dextrose, indicating similar pancreatic capacity for both groups of ponies, but after oral dextrose the area under the curve was markedly higher for hyperinsulinaemic ponies, indicating a greater secretion rate of these peptides. Slower insulin clearance might have also contributed to the larger AUC in HI ponies, but this hypothesis requires further investigation with specific measures of hepatic insulin clearance.

Obese horses have high insulin and C-peptide levels but lower C-peptide to insulin ratios than non-obese horses, indicating both increased insulin secretion by the pancreas and reduced clearance of insulin by the liver.
Toth et al. 2010 suggested that plasma insulin alone may not be a good measure of pancreatic beta cell function, because liver clearance of insulin may be reduced in some horses with insulin dysregulation, leading to higher and longer plasma insulin concentrations, suggesting that C c-peptide should be measured at the same time.
Tóth F, Frank N, Martin-Jiménez T, Elliott SB, Geor RJ, Boston RC
Measurement of C-peptide concentrations and responses to somatostatin, glucose infusion, and insulin resistance in horses
Equine Vet J. 2010 Mar;42(2):149-55
"CONCLUSIONS:Endogenous C-peptide secretion decreases in response to somatostatin and increases after dextrose infusion. Results suggest that relative insulin clearance decreases as pancreatic secretion increases in response to dextrose infusion. Hyperinsulinaemia in insulin resistant horses may be associated with both increased insulin secretion and decreased insulin clearance.
POTENTIAL RELEVANCE:Both C-peptide and insulin concentrations should be measured to assess pancreatic secretion and insulin clearance in horses."

C-peptide: Roles in diabetes, insulinoma, and hypoglycemia - Tricia A. Bal - www.siemens.com 2009

Stability of C-Peptide

McDonald TJ, Perry MH, Peake RWA, Pullan NJ, O'Connor J, Shields BM, Knight BA, Hattersley AT
EDTA Improves Stability of Whole Blood C-Peptide and Insulin to Over 24 Hours at Room Temperature
PLOS ONE July 2012

Cresty neck

Horses with insulin dysregulation and EMS often store fat along their neck crest - this is described as a cresty neck.

The cresty neck score (CNS) gives a numerical score according to description of the nuchal fat accumulation along the top of the neck. Neck crest (or nuchal) fat is not necessarily found in proportion to overall body fat or body condition score (BCS), and therefore the CNS can be used as an independent measure of adiposity. The CNS has been validated against nuchal fat thickness. The CNS should be assessed by looking at and feeling the neck.

Body condition scoring and cresty neck scoring - CARE About Laminitis

How to assign a cresty neck score to a horse/pony - Queensland University of Technology

Fitzgerald DM, Anderson ST, Sillence MN, de Laat MA.
The cresty neck score is an independent predictor of insulin dysregulation in ponies.
PLoS One. 2019 Jul 24;14(7):e0220203. doi: 10.1371/journal.pone.0220203. PMID: 31339945; PMCID: PMC6655749.
"Cresty neck score was more predictive of insulin dysregulation than BCS, and this may be relevant to the diagnosis of EMS."

Giles SL, Nicol CJ, Rands SA, Harris PA.
Assessing the seasonal prevalence and risk factors for nuchal crest adiposity in domestic horses and ponies using the Cresty Neck Score.
BMC Vet Res 11, 13 (2015). https://doi.org/10.1186/s12917-015-0327-7

Burns TA, Geor RJ, Mudge MC, McCutcheon LJ, Hinchcliff KW, Belknap JK
Proinflammatory cytokine and chemokine gene expression profiles in subcutaneous and visceral adipose tissue depots of insulin-resistant and insulin-sensitive light breed horses
J Vet Intern Med. 2010 Jul-Aug;24(4):932-9 (PubMed)
"the nuchal ligament depot has unique biological behavior in the horse and is more likely to adopt an inflammatory phenotype than other depots examined."

Carter RA, Geor RJ, Burton Staniar W, Cubitt TA, Harris PA.
Apparent adiposity assessed by standardised scoring systems and morphometric measurements in horses and ponies.
Vet J. 2009 Feb;179(2):204-10. doi: 10.1016/j.tvjl.2008.02.029. Epub 2008 Apr 28. PMID: 18440844.

Photos of examples of different cresty neck scores

Management Techniques for Equine Health and Proper Feeding Procedures - Penn State Extension slides 28 to 34

Cresty Neck Scoring - Baileys Horse Feeds

CRH - Corticotropin-Releasing Hormone

European Journal of Endocrinology (2006) 155 S71–S76
Corticotropin-releasing hormone physiology
Joseph A Majzoub

Cryotherapy/digital hypothermia (cold therapy/icing the feet)

Cryotherapy or digital hypothermia is the only treatment proven to prevent and ameliorate laminitis in both experimental and naturally occurring sepsis related laminitis (SRL) cases, i.e. where laminitis is linked to inflammation (e.g. colitis, retained placenta, pleuropneumonia, endotoxaemia). Cooling the foot may reduce the delivery of "laminitis trigger factors" to the foot, and has been shown to reduce markers of inflammation. Surrounding the feet with iced water or ice has been shown to lower hoof temperature to around 11-12'C within 2 hours.

Research published by Stokes et al. in 2019 has shown that continuously icing one foot before inducing laminitis with high levels of insulin reduces cellular damage and the severity of laminitis. However, it isn't yet known whether icing the feet will prevent or reduce the severity of naturally occurring endocrinopathic laminitis.

Nonstop icing for 72 hours (and even longer) has been well tolerated. Use buckets, soaking boots, or make a paddling pool for the horse to stand in.

Cassimeris L, Armstrong C, Burger QC, Stokes S, van Eps A, Galantino-Homer H
Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia
Veterinary Immunology and Immunopathology Volume 241, November 2021, 110326. https://doi.org/10.1016/j.vetimm.2021.110326

Stokes, SM, Burns, TA, Watts, MR, Bertin F-R, Stefanovski D, Medina-Torres CE, Belknap JK, van Eps AW
Effect of digital hypothermia on lamellar inflammatory signaling in the euglycemic hyperinsulinemic clamp laminitis model
J Vet Intern Med. published online 25 June 2020; 1– 8. https://doi.org/10.1111/jvim.15835

Dern K, Burns TA, Watts MR, van Eps AW, Belknap JK
Influence of digital hypothermia on lamellar events related to IL-6/gp130 signalling in equine sepsis-related laminitis
Equine Vet J. May 2020;52(3):441‐448. Published online 24 October 2019. doi:10.1111/evj.13184

Stokes SM, Belknap JK, Engiles JB, Stefanovski D, Bertin FR, Medina-Torres CE, Horn R, van Eps AW
Continuous digital hypothermia prevents lamellar failure in the euglycaemic hyperinsulinaemic clamp model of equine laminitis
Equine Vet J. 2019 Jan 13. doi: 10.1111/evj.13072. [Epub ahead of print]
8 healthy Standardbred horses had endocrinopathic laminitic induced using the euglycaemic hyperinsulinaemic clamp model (EHC) (giving and causing high levels of insulin). From the time the insulin adminstration was started, one forelimb was kept continuously iced, and the other forelimb was untreated (so at ambient temperature). After 48 hours of high insulin treatment, samples were taken from the top, middle and bottom of the laminae in the toe area, examined under a microscope, and given a score of 0 (least damage) to 3 (most damage).
All of the untreated (ambient) feet had severe elongation and disruption of the secondary epidermal laminae, with separation of the laminae, but this was not seen in any of the iced feet. 92% of the untreated feet samples scored 3, and the remaining 8% scored 2. 50% of the iced feet samples scored 1, and 50% scored 2. Primary epidermal laminae were significantly longer in untreated feet compared to iced feet. Cellular proliferation was significantly increased in untreated feet compared to iced feet.
"Conclusions: Continuous digital hypothermia reduced the severity of laminitis in the EHC model and prevented histological lesions compatible with lamellar structural failure."
NB This research does not suggest that icing is appropriate for naturally occurring endocrinopathic laminitis - this is not yet known. In this research the feet were iced before signs of laminitis were seen (as soon as insulin concentrations exceeded normal levels), and it is recognized that the EHC model of laminitis, where insulin concentrations remain constantly at abnormally high levels, may not mimic naturally occurring endocrinopathic laminitis.

Burke MJ, Tomlinson JE, Blikslager AT, Johnson AL, Dallap‐Schaer BL
Evaluation of digital cryotherapy using a commercially available sleeve style ice boot in healthy horses and horses receiving i.v. endotoxin
EVJ Nov 2018 Vol 50, Issue 6 Pages 848-853. Published online 13 April 2018. https://doi.org/10.1111/evj.12842
See also Equine cryotherpay device likely to be effective in treating laminitis - Cornell University College of Veterinary Medicine May 2019

Morgan J, Stefanovski D, Lenfest M, Chatterjee S, Orsini J
Novel dry cryotherapy system for cooling the equine digit
Vet Rec Open. 2018 Jan 7;5(1):e000244. doi: 10.1136/vetreco-2017-000244. eCollection 2018 (PubMed)

Dern K, van Eps A, Wittum T, Watts M, Pollitt C, Belknap J
Effect of Continuous Digital Hypothermia on Lamellar Inflammatory Signaling When Applied at a Clinically-Relevant Timepoint in the Oligofructose Laminitis Model
J Vet Intern Med. 2018 Jan;32(1):450-458 (Online 27 Dec 2017). doi: 10.1111/jvim.15027

van Eps AW, Orsini JA
A comparison of seven methods for continuous therapeutic cooling of the equine digit
EVJ Jan 2016 Vol 48, Issue 1 Pages 120-124. Published onlinse 11 November 2014. https://doi.org/10.1111/evj.12384
7 foot cooling methods were compared - "immersion of the foot and at least the pastern region in ice and water achieved sustained HWST <10°C as did a prototype perfused cuff device with a dry interface. Variation between cooling methods may have a profound effect on HWST and therefore efficacy in clinical cases where laminitis prophylaxis or therapy is the goal."

See also: Which Cryotherapy Method Works Best for Cooling Hooves? Katie Navarra thehorse.com Jan 2015

Cold Therapy of Feet for Laminitis Prevention - Doug Thal - Horse Side Vet Guide

van Eps AW1, Pollitt CC, Underwood C, Medina-Torres CE, Goodwin WA, Belknap JK
Continuous digital hypothermia initiated after the onset of lameness prevents lamellar failure in the oligofructose laminitis model
Equine Vet J. 2014 Sep;46(5):625-30. doi: 10.1111/evj.12180. Epub 2013 Nov 29
"Conclusions: Digital hypothermia reduced the severity of lamellar injury and prevented lamellar structural failure (complete dermoepidermal separation) when initiated at the detection of lameness in an acute laminitis model. This study provides the first evidence to support the use of therapeutic digital hypothermia as a treatment for acute laminitis."

EQUINE LATE BREAKING RESEARCH REPORT SUBMISSIONS 2012 ACVIM FORUM
Digital hypothermia applied after the onset of lameness prevents lamellar failure in the oligofructose laminitis model
Andrew van Eps
Icing the feet reduced the damage caused by laminitis when started at the first signs of lameness.

Equine Vet J. 2012 Mar;44(2):230-7. doi: 10.1111/j.2042-3306.2011.00416.x. Epub 2011 Sep 5. (PubMed)
Digital hypothermia inhibits early lamellar inflammatory signalling in the oligofructose laminitis model.
VAN Eps AW, Leise BS, Watts M, Pollitt CC, Belknap JK.
"Conclusions: Digital hypothermia effectively blocked early lamellar inflammatory events likely to play an important role in lamellar injury including the expression of chemokines, proinflammatory cytokines, COX-2 and endothelial adhesion molecules.
Potential relevance: This study demonstrates a potential mechanism by which hypothermia reduces the severity of acute laminitis, and may help identify molecular targets for future laminitis intervention."

Cryotherapy Methods to Treat Laminitis - theHORSE.com Nov 2011

Equine vet. J. (2009) 41 (8) 741-746
Equine laminitis model: Cryotherapy reduces the severity of lesions evaluated seven days after induction with oligofructose
Van Eps AW, Pollitt CC

Pollitt CC, van Eps AW
Prolonged, continuous distal limb cryotherapy in the horse
Equine Vet J. 2004 Apr;36(3):216-20

Putting out the Fire - Laminitis Prevention
Christopher C Pollitt

CT - computed tomography

CT imaging is commonly being used in horses to scan the head and pituitary gland, and may help increase our understanding of PPID and changes to the pituitary gland.

The University of Liverpool's Philip Leverhulme Equine Hospital has a large animal, large bore sliding gantry CT system, which can be used for scanning the heads and top of the neck in standing sedated horses, as well as horses under anaesthetic.
See Unique CT Scanner Unveiled - Vet Times 07 August 2018

CT imaging is available for horses in the UK at these and other veterinary hospitals and clinics:
University of Liverpool Equine Hospital: Computed Tomography
RVC: RVC revolutionise equine imaging with first specialised CT scan for horses - March 2016
Liphook Equine Hospital: CT - Computed Tomography - May 2016
Rossdales: Computed Tomography
B&W Equine Vets: Computed Tomography (CT) Scan
Sussex Equine Hospital: Computed Tomography

Computed Tomography of the Equine Head - Sarah Powell, Absolute Horse February 2012

Pease AP, Schott HC 2nd, Howey EB, Patterson JS
Computed tomographic findings in the pituitary gland and brain of horses with pituitary pars intermedia dysfunction
J Vet Intern Med. 2011 Sep-Oct;25(5):1144-51
"CT is a useful imaging modality to determine pituitary gland size of PPID-affected horses,and CT measurements are similar to gross pathologic measurements."

Kruger EF, Puchalski SM, Pollard RE, Galuppo LD, Hornof WJ, Wisner ER
Measurement of equine laminar blood flow and vascular permeability by use of dynamic contrast-enhanced computed tomography
Am J Vet Res. 2008 Mar;69(3):371-7. doi: 10.2460/ajvr.69.3.371

Cyproheptadine

Cyproheptadine is a serotonin antagonist, anticholinergic and anti-histamine. Serotonin is thought to stimulate PI melanotropes to produce POMC (serotonin increases POMC activity). Perkins found that both pergolide and cyproheptadine lower plasma ACTH concentrations in horses with PPID, but Donaldson found that pergolide is more effective (see below). Horses treated with cyproheptadine may show signs of sedation when treatment starts. The recommended dose appears to be 0.25 mg /kg bodyweight by mouth every 12 hours or 0.5 mg/kg bodyweight every 24 hours, and it can be given either alone or in combination with pergolide once a high dose of pergolide has been reached.

Medsafe data sheet - Cyproheptadine
Anticholinergic side-effects of Cyproheptadine (in humans) - doublecheckmd

From the Equine Endocrinology Group's Recommendations for the Diagnosis and Treatment of PPID 2017:
"Treatment strategies used by the group for refractory cases include gradually increasing the pergolide dosage to 3 mg for a 500-kg horse (6 mg/kg) daily and adding cyproheptadine (0.25 mg/kg orally twice daily or 0.5 mg/kg once daily) or gradually increasing the pergolide dosage up to 5 mg for a 500-g horse (10 mg/kg) daily."

From TLS notes of Boehringer Ingelheim webinar 04 September 2012 - Andy Durham - Current thoughts of where we are with PPID diagnostics:
Horses that don’t respond to the maximum dose (10 µg/kg) could either carry on with an affordable dose in the hope that they will eventually respond, or try adding cyproheptadine (0.25 mg/kg every 12 hrs) to the pergolide.

From TLS notes of TheHorse.com's Ask the Vet LIVE event on equine Cushing's disease (PPID) 18 September 2012:
Q. How should PPID be managed?
Whole horse approach – drug therapy with pergolide, plus hoof care, nutrition – insulin status, deworming, clipping, dental checks, exercise if possible. Pergolide 1st line, if don’t respond at higher doses cyproheptadine may be added. More than just drug therapy – stay on top of all issues that affect PPID horse.

In his "Update on headshaking in equine patients" published in Vet Times November 2017, David Rendle discussed cyproheptadine at a dose of 0.3 mg/kg by mouth twice a day as a possible treatment for trigeminal-mediated headshaking (TMH), as it has "antihistaminic, anticholinergic, antiserotonergic and calcium channel-blocking activity", and stated that "50% of horses treated with cyproheptadine experience adverse effects, including lethargy, drowsiness and anorexia."

Durham Andy
An update on the diagnosis and treatment of Equine Cushing's Disease
IVIS - BEPS 19 November 2011

Durham A
The pharmacologic basis for the treatment of endocrinopathic laminitis
Vet Clin North Am Equine Pract. 2010 Aug;26(2):303-14
Full paper

Management of Pituitary Pars Intermedia Dysfunction (PPID) - Nicholas Frank 2011

Pituitary Pars Intermedia Dysfunction: Diagnosis and Treatment - Nicholas Frank
FAEP 49th Annual Ocala Equine Conference - 21-24 Oct 2011, Florida

The PPID Working Group's Diagnosis and Treatment of Pituitary Pars Intermedia Dysfunction booklet - see Table 6
"Cyproheptadine can be administered in combination (0.25 mg/kg orally every 12 h or 0.5 mg/kg every 24 h) with pergolide once the maximum dosage has been attained."

Abra Wright MSc Thesis 2009 (page 17)
Pharmacokinetics of Pergolide in normal mares

Thomas J Divers
Pergolide and Cyproheptadine: Which Medication to Choose for Treatment of Equine Cushing's Disease?
Journal of Equine Veterinary Science Vol 28 No 6 (2008)

J Vet Intern Med 2002 Nov-Dec;16(6):742-6.
Treatment with pergolide or cyproheptadine of pituitary pars intermedia dysfunction (equine Cushing's disease).
Donaldson M, LaMonte B, Morresey P, Smith G, Beech J
Medical records of 27 horses (including 13 ponies) treated with pergolide or cyproheptadine for pituitary pars intermedia dysfunction were reviewed to determine the effect of treatment on plasma ACTH, insulin, and glucose concentrations and clinical signs. All horses treated with cyproheptadine were given 0.25 mg/kg p.o. q24h. After pergolide treatment, ACTH concentrations (n = 20; median = 30.4 pg/ml; range, 4.2-173) were significantly lower (P < .01) than those in horses treated with cyproheptadine (n = 7; median = 141.0 pg/ml: range, 10-1,230). Significantly (P = .02) more owners of horses treated with pergolide (85%, 17/20) reported an improvement in clinical signs compared to owners of horses treated with cyproheptadine (28%, 2/7).

Perkins GA, Lamb S, Erb HN, Schanbacher B, Nydam DV, Divers TJ
Plasma adrenocorticotropin (ACTH) concentrations and clinical response in horses treated for equine Cushing's disease with cyproheptadine or pergolide
Equine Vet J. 2002 Nov;34(7):679-85

AAEP 2001
The Michigan Cushing’s Project
Schott H, Coursen C, Eberhart S, Nachreiner R, Refsal K, Ewart S, Marteniuk J
"the results clearly demonstrate that treatment with pergolide produced clinical and laboratory responses that were superior to treatment with cyproheptadine. In fact, treatment with cyproheptadine was found to be of little benefit when responses were compared with those observed in horses receiving no treatment."

See p8 of AAVPT monograph for Pergolide for a summary of the Donaldson et al. 2002 and Schott et al 2001 papers.

The Merck Veterinary Manual: "Cyproheptadine is an antihistamine with antiserotonin action. It promotes appetite by inhibition at the serotoninergic receptors, which control satiety."

TLS note: we have heard of one case where a horse that was ill (with a probably bacterial infection) and significantly losing weight was given Periactin (Cyproheptadine) as an appetite stimulant for the first couple of weeks while starting on Prascend (the horse had previously been tried on Prascend and gone off feed). No side effects of either Prascend or Periactin were seen.

Cytokines

Animals 2012, 2(2), 243-260 (Full)
A Potential Role for Pro-Inflammatory Cytokines in the Development of Insulin Resistance in Horses
Jessica K. Suagee, Benjamin A. Corl and Raymond J. Geor

J Vet Intern Med. 2008 Mar-Apr;22(2):436-42. (PubMed)
Cytokine dysregulation in aged horses and horses with pituitary pars intermedia dysfunction.McFarlane D, Holbrook TC.
"BACKGROUND: Equine pituitary pars intermedia dysfunction (PPID) is the result of a loss of dopaminergic inhibition of the pars intermedia secondary to neurodegeneration of periventricular hypothalamic neurons. The pathologic events contributing to development of neurodegeneration or clinical signs in equids with PPID are unknown. Chronic inflammation may contribute to initiation or progression of PPID.
HYPOTHESIS: Horses with PPID have a distinct systemic cytokine profile compared with that of normal adult or aged horses. The cytokine profile of healthy aged horses differs from that of adult horses.
ANIMALS: Aged horses with PPID, healthy aged-matched controls, and adult controls (n = 14 per group).

METHODS: Total leukocyte cytokine expression was determined by quantitative polymerase chain reaction (PCR), and tumor necrosis factor (TNF)-alpha plasma concentration was determined by enzyme-linked immunosorbent assay (ELISA). Peripheral blood mononuclear cell (PBMC) TNF-alpha response after endotoxin (lipopolysaccharide [LPS]) treatment was assessed by ELISA.

RESULTS: Aged healthy horses had increased expression of interleukin (IL)-6, IL-8, and interferon-gamma as well as PBMC TNF-alpha release after LPS stimulation compared with healthy adult horses. In contrast, aged horses with PPID had increased IL-8 expression, but expression of other cytokines was similar to that of healthy adult horses, not age-matched controls.

CONCLUSIONS AND CLINICAL IMPORTANCE: Aged horses show evidence of a proinflammatory state that may contribute to development of age-associated diseases. Horses with PPID have increased expression of IL-8, which may influence the ability of horses with PPID to respond to bacterial pathogens. The general decrease in proinflammatory cytokine expression observed in horses with PPID may be the outcome of high plasma concentrations of anti-inflammatory hormones."

Treiber K, Carter R, Gay L, Williams C, Geor .
Inflammatory and redox status of ponies with a history of pasture-associated laminitis
Vet Immunol Immunopathol. 2009 Jun 15;129(3-4):216-20 (PubMed)